tbuckley/cabot-search huggingface dataset:
Glycemic Control Over Multiple Decades and Dementia Risk in People With Type 2 Diabetes
Authors: Chris Moran, Mary E. Lacy, Rachel A. Whitmer, Ai-Lin Tsai, Charles P. Quesenberry, Andrew J. Karter, Alyce S. Adams, Paola Gilsanz
Journal: JAMA Neurology (2023)

Importance The levels of glycemic control associated with the lowest risk of dementia in people with type 2 diabetes are unknown. This knowledge is critical to inform patient-centered glycemic target setting. Objective To examine the associations between cumulative exposure to various ranges of glycated hemoglobin (HbA 1c ) concentrations with dementia risk across sex and racial and ethnic groups and the association of current therapeutic glycemic targets with dementia risk. Design, Setting, and Participants This cohort study included members of the Kaiser Permanente Northern California integrated health care system with type 2 diabetes who were aged 50 years or older during the study period from January 1, 1996, to September 30, 2015. Individuals with fewer than 2 HbA 1c measurements during the study period, prevalent dementia at baseline, or less than 3 years of follow-up were excluded. Data were analyzed from February 2020 to January 2023. Exposures Time-updated cumulative exposure to HbA 1c thresholds. At each HbA 1c measurement, participants were categorized based on the percentage of their HbA 1c measurements that fell into the following categories: less than 6%, 6% to less than 7%, 7% to less than 8%, 8% to less than 9%, 9% to less than 10%, and 10% or more of total hemoglobin (to convert percentage of total hemoglobin to proportion of total hemoglobin, multiply by 0.01). Main Outcomes and Measures Dementia diagnosis was identified using International Classification of Diseases, Ninth Revision codes from inpatient and outpatient encounters. Cox proportional hazards regression models estimated the association of time-varying cumulative glycemic exposure with dementia, adjusting for age, race and ethnicity, baseline health conditions, and number of HbA 1c measurements. Results A total of 253 211 participants were included. The mean (SD) age of participants was 61.5 (9.4) years, and 53.1% were men. The mean (SD) duration of follow-up was 5.9 (4.5) years. Participants with more than 50% of HbA 1c measurements at 9% to less than 10% or 10% or more had greater risk of dementia compared with those who had 50% or less of measurements in those categories (HbA 1c 9% to &amp;amp;lt;10%: adjusted hazard ratio [aHR], 1.31 [95% CI, 1.15-1.51]; HbA 1c ≥10%: aHR, 1.74 [95% CI, 1.62-1.86]). By contrast, participants with more than 50% of HbA 1c concentrations less than 6%, 6% to less than 7%, or 7% to less than 8% had lower risk of dementia (HbA 1c &amp;amp;lt;6%: aHR, 0.92 [95% CI, 0.88-0.97]; HbA 1c 6% to &amp;amp;lt;7%: aHR, 0.79 [95% CI, 0.77-0.81]; HbA 1c 7% to &amp;amp;lt;8%: aHR, 0.93 [95% CI, 0.89-0.97]). Conclusions and Relevance In this study dementia risk was greatest among adults with cumulative HbA 1c concentrations of 9% or more. These results support currently recommended relaxed glycemic targets for older people with type 2 diabetes.
Prurigo nodularis is highly linked with neural sensitization disorders of pain among hospitalized adults in the United States – National Inpatient Sample 2016–2019
Authors: Siri Choragudi, Gil Yosipovitch
Journal: British Journal of Dermatology (2023)

This study demonstrates a high association between prurigo nodularis (PN) and central neural sensitization diseases of pain, such as fibromyalgia, chronic interstitial cystitis and irritable bowel syndrome – possibly indicating that further research is needed to compare the role of neural sensitization in central diseases of pain to the role of neural sensitization in PN.
Caspase 1 Enhances Transport and Golgi Organization Protein 1 Expression to Promote Procollagen Export From the Endoplasmic Reticulum in Systemic Sclerosis Contributing to Fibrosis
Authors: Lianne M. Connolly, Caya M. McFalls, Isabelle G. McMahon, Akash M. Bhat, Carol M. Artlett
Journal: Arthritis & Rheumatology (2023)

Objective Transport and Golgi Organization protein 1 (TANGO1) is a protein that regulates the export of procollagen from the endoplasmic reticulum and has a role in the organization of exit sites for general protein export. What regulates the expression of TANGO1 and the role of TANGO1 in fibrosis is poorly understood and has never been studied in the setting of systemic sclerosis (SSc). We undertook this study to determine the role of TANGO1 in SSc fibrosis. Methods SSc (n = 15) and healthy (n = 12) primary fibroblast lung cell lines were investigated for the expression of TANGO1. Histologic analyses for TANGO1 were performed on lung biopsy samples (n = 12 SSc patient samples and n = 8 healthy control samples). Results SSc fibroblasts showed increased expression of TANGO1 protein in cultured fibroblasts. TANGO1 colocalizes with α‐smooth muscle actin (α‐SMA)–positive cells in SSc lung tissue and is highly up‐regulated in the neointima of SSc vessels. TANGO1 expression was dependent on the inflammasome activation of caspase 1. It was also dependent on signaling from the interleukin‐1 (IL‐1) and transforming growth factor β (TGFβ) receptors. The decrease in TANGO1 down‐regulated export of larger cargos including collagen and laminin. Reduced TANGO1 protein had no effect on smaller molecular weight cargoes; however, the secretion of elastin was significantly reduced. Conclusion TANGO1 is markedly increased in SSc fibroblasts and was found to be elevated in lung tissue in association with α‐SMA–positive cells. TANGO1 expression is driven by inflammasome‐dependent caspase 1 activation and is mediated by IL‐1 and TGFβ downstream signaling. These observations suggest that during fibrosis, caspase 1 promotes the up‐regulation of TANGO1 and the organization of endoplasmic reticulum exits sites, ultimately contributing to procollagen export and fibrosis. image
Dexamethasone for Inpatients With COVID-19 in a National Cohort
Authors: Ahmad Mourad, Dylan Thibault, Thomas L. Holland, Siyun Yang, Allison R. Young, Shanna A. Arnold Egloff, Laine E. Thomas
Journal: JAMA Network Open (2023)

Importance Limited effective therapeutics are available to hospitalized patients with COVID-19. Clinical trials and observational studies have shown varying effects of systemic corticosteroids, including dexamethasone, in hospitalized patients with COVID-19, with limited descriptions of important patient subgroups. Objective To examine the clinical use of dexamethasone for hospitalized patients with COVID-19 respiratory illness and to explore the heterogeneity of treatment outcomes across different subgroups. Design, Setting, and Participants This is a retrospective, propensity score–weighted cohort study of adult patients hospitalized for at least 48 hours for COVID-19 respiratory illness between July 1, 2020, and October 31, 2021, at a large health care network of 156 hospitals across the US. Data analysis was performed from March 2022 to February 2023. Exposures Systemic dexamethasone administered within 48 hours of either admission or escalation in oxygen support. Main Outcomes and Measures All-cause in-hospital mortality or discharge to hospice. Results A total of 80 699 patients who met the eligibility criteria were identified (median [IQR] age, 64 [52-76] years; 37 606 women [46.6%]); 13 230 patients (16.4%) identified as Black, 49 222 (60.9%) as White, 18 247 (22.6%) as other race, and 20 340 (25.2%) as Hispanic ethnicity. Of these patients, 13 040 (16.2%) did not require supplemental oxygen within 48 hours of admission, 56 368 (69.8%) required supplemental oxygen, 7618 (9.4%) required noninvasive positive pressure ventilation (NIPPV), and 3673 (4.6%) required mechanical ventilation (MV) and/or extracorporeal membrane oxygenation (ECMO). After adjustment by propensity score overlap weighting, early use of dexamethasone was associated with reduction in a composite outcome of in-hospital mortality or discharge to hospice for patients receiving supplemental oxygen (aOR, 0.92; 95% CI, 0.86-0.98) and MV and/or ECMO (aOR, 0.82; 95% CI, 0.68-0.99). In contrast, all-cause inpatient mortality or discharge to hospice was not lower for patients who received dexamethasone in the no supplemental oxygen group (aOR, 0.90; 95% CI, 0.78-1.03) and in the NIPPV group (aOR, 0.87; 95% CI, 0.73-1.04). Importantly, patients with more comorbidities had greater benefit from dexamethasone use. Conclusions and Relevance In this national multicenter cohort study of inpatients with COVID-19, early administration of dexamethasone was associated with significantly reduced odds of mortality or discharge to hospice in those requiring supplemental oxygen or MV and/or ECMO but not in those requiring no supplemental oxygen or NIPPV. These results support the continued use of systemic dexamethasone in patients hospitalized with COVID-19.
Prevalence and characteristics of long COVID in elderly patients: An observational cohort study of over 2 million adults in the US
Authors: Kin Wah Fung, Fitsum Baye, Seo H. Baik, Zhaonian Zheng, Clement J. McDonald
Journal: PLoS Medicine (2023)

Incidence of long COVID in the elderly is difficult to estimate and can be underreported. While long COVID is sometimes considered a novel disease, many viral or bacterial infections have been known to cause prolonged illnesses. We postulate that some influenza patients might develop residual symptoms that would satisfy the diagnostic criteria for long COVID, a condition we call "long Flu." In this study, we estimate the incidence of long COVID and long Flu among Medicare patients using the World Health Organization (WHO) consensus definition. We compare the incidence, symptomatology, and healthcare utilization between long COVID and long Flu patients.
FOXA2 Cooperates with Mutant KRAS to Drive Invasive Mucinous Adenocarcinoma of the Lung
Authors: Koichi Tomoshige, William D. Stuart, Iris M. Fink-Baldauf, Masaoki Ito, Tomoshi Tsuchiya, Takeshi Nagayasu, Tomoki Yamatsuji, Morihito Okada, Takuya Fukazawa, Minzhe Guo, Yutaka Maeda
Journal: Cancer Research (2023)

Abstract The endoderm-lineage transcription factor FOXA2 has been shown to inhibit lung tumorigenesis in in vitro and xenograft studies using lung cancer cell lines. However, FOXA2 expression in primary lung tumors does not correlate with an improved patient survival rate, and the functional role of FOXA2 in primary lung tumors remains elusive. To understand the role of FOXA2 in primary lung tumors in vivo, here, we conditionally induced the expression of FOXA2 along with either of the two major lung cancer oncogenes, EGFRL858R or KRASG12D, in the lung epithelium of transgenic mice. Notably, FOXA2 suppressed autochthonous lung tumor development driven by EGFRL858R, whereas FOXA2 promoted tumor growth driven by KRASG12D. Importantly, FOXA2 expression along with KRASG12D produced invasive mucinous adenocarcinoma (IMA) of the lung, a fatal mucus-producing lung cancer comprising approximately 5% of human lung cancer cases. In the mouse model in vivo and human lung cancer cells in vitro, FOXA2 activated a gene regulatory network involved in the key mucous transcription factor SPDEF and upregulated MUC5AC, whose expression is critical for inducing IMA. Coexpression of FOXA2 with mutant KRAS synergistically induced MUC5AC expression compared with that induced by FOXA2 alone. ChIP-seq combined with CRISPR interference indicated that FOXA2 bound directly to the enhancer region of MUC5AC and induced the H3K27ac enhancer mark. Furthermore, FOXA2 was found to be highly expressed in primary tumors of human IMA. Collectively, this study reveals that FOXA2 is not only a biomarker but also a driver for IMA in the presence of a KRAS mutation. Significance: FOXA2 expression combined with mutant KRAS drives invasive mucinous adenocarcinoma of the lung by synergistically promoting a mucous transcriptional program, suggesting strategies for targeting this lung cancer type that lacks effective therapies.
Dimeric p53 Mutant Elicits Unique Tumor-Suppressive Activities through an Altered Metabolic Program
Authors: Jovanka Gencel-Augusto, Xiaoping Su, Yuan Qi, Elizabeth M. Whitley, Vinod Pant, Shunbin Xiong, Vrutant Shah, Jerome Lin, Encarnacion Perez, Marta L. Fiorotto, Iqbal Mahmud, Abhinav K. Jain, Philip L. Lorenzi, Nicholas E. Navin, Ellen R. Richie, Guillermina Lozano
Journal: Cancer Discovery (2023)

Abstract Cancer-related alterations of the p53 tetramerization domain (TD) abrogate wild-type (WT) p53 function. They result in a protein that preferentially forms monomers or dimers, which are also normal p53 states under basal cellular conditions. However, their physiologic relevance is not well understood. We have established in vivo models for monomeric and dimeric p53, which model Li–Fraumeni syndrome patients with germline p53 TD alterations. p53 monomers are inactive forms of the protein. Unexpectedly, p53 dimers conferred some tumor suppression that is not mediated by canonical WT p53 activities. p53 dimers upregulate the PPAR pathway. These activities are associated with lower prevalence of thymic lymphomas and increased CD8+ T-cell differentiation. Lymphomas derived from dimeric p53 mice show cooperating alterations in the PPAR pathway, further implicating a role for these activities in tumor suppression. Our data reveal novel functions for p53 dimers and support the exploration of PPAR agonists as therapies. Significance: New mouse models with TP53R342P (monomer) or TP53A347D (dimer) mutations mimic Li–Fraumeni syndrome. Although p53 monomers lack function, p53 dimers conferred noncanonical tumor-suppressive activities. We describe novel activities for p53 dimers facilitated by PPARs and propose these are “basal” p53 activities. See related commentary by Stieg et al., p. 1046. See related article by Choe et al., p. 1250. This article is highlighted in the In This Issue feature, p. 1027
Effect of intravenous iron replacement on recurrent heart failure hospitalizations and cardiovascular mortality in patients with heart failure and iron deficiency: A Bayesian <scp>meta‐analysis</scp>
Authors: Stefan D. Anker, Muhammad Shahzeb Khan, Javed Butler, Stephan von Haehling, Ewa A. Jankowska, Piotr Ponikowski, Tim Friede
Journal: European Journal of Heart Failure (2023)

Abstract Aims Iron deficiency is common in patients with heart failure (HF) and reduced ejection fraction (HFrEF) and is associated with a poor prognosis. Whether intravenous iron replacement improves recurrent HF hospitalizations and cardiovascular mortality of these patients is uncertain although several trials were conducted. Moreover, none of the trials were powered to assess the effect of intravenous iron in clinically important subgroups. Therefore, we conducted a Bayesian analysis to derive precise estimates of the effect of intravenous iron replacement on recurrent HF hospitalizations and cardiovascular mortality in iron‐deficient HFrEF patients using consistent subgroup definitions across trials. Methods and results Individual participant data were used from the FAIR‐HF ( n = 459), CONFIRM‐HF (n = 304) and AFFIRM‐AHF ( n = 1108) trials. These data were re‐analysed following as closely as possible the approach taken in the analyses of IRONMAN ( n = 1137), for which study level data were used. Definitions of outcomes and subgroups from the FAIR‐HF, CONFIRM‐HF and AFFIRM‐AHF were matched with those used in IRONMAN. The primary endpoint was recurrent HF hospitalizations and cardiovascular mortality. The analysis of recurrent events was based on rate ratios (RR) derived from the Lin‐Wei‐Yang‐Ying model, and the data were pooled using Bayesian random‐effects meta‐analysis. Compared with placebo, intravenous iron significantly reduced the rates of recurrent HF hospitalizations and cardiovascular mortality (RR 0.73, 95% credible interval [CI] 0.48–0.99; between‐trial heterogeneity tau = 0.16). The pooled treatment effects did not provide evidence for any differential effects for subgroups based on sex (ratio of rate ratios [RRR] 1.49 [95% CI 0.95–2.37], age &lt;69.4 vs. ≥69.4 years) (RRR 0.68 [0.40–1.15]), ischaemic versus non‐ischaemic aetiology of HF (RRR 0.73 [0.42–1.33]), transferrin saturation &lt;20% vs. ≥20% (RRR 0.75 [0.40–1.34]), estimated glomerular filtration rate ≤60 versus &gt;60 ml/min/1.73 m 2 (RRR 0.97 [0.56–1.68]), haemoglobin &lt;11.8 versus ≥11.8 (RRR 0.95 [0.53–1.60]), ferritin &lt;35 versus ≥35 μg/L (RRR 1.26 [0.72–2.48]) and New York Heart Association class II versus III/IV (RRR 0.91 [0.54–1.56]). Conclusions Treatment of iron‐deficient HFrEF patients with intravenous iron – namely with ferric carboxymaltose or ferric derisomaltose – results in significant reduction in recurrent HF hospitalizations and cardiovascular mortality. Results were nominally consistent across the subgroups studied, but for several of these subgroups uncertainty remains present.
Transfer of nuclear and ribosomal material from Sox10-lineage cells to neurons in the mouse brain
Authors: Florian Mayrhofer, Angela M. Hanson, Manuel F. Navedo, Yang K. Xiang, Athena M. Soulika, Wenbin Deng, Olga V. Chechneva
Journal: The Journal of Experimental Medicine (2023)

Material transfer is an essential form of intercellular communication to exchange information and resources between cells. Material transfer between neurons and from glia to neurons has been demonstrated to support neuronal survival and activity. Understanding the extent of material transfer in the healthy nervous system is limited. Here we report that in the mouse central nervous system (CNS), neurons receive nuclear and ribosomal material of Sox10-lineage cell (SOL) origin. We show that transfer of SOL-derived material to neurons is region dependent, establishes during postnatal brain maturation, and dynamically responds to LPS-induced neuroinflammation in the adult mouse brain. We identified satellite oligodendrocyte-neuron pairs with loss of plasma membrane integrity between nuclei, suggesting direct material transfer. Together, our findings provide evidence of regionally coordinated transfer of SOL-derived nuclear and ribosomal material to neurons in the mouse CNS, with potential implications for the understanding and modulation of neuronal function and treatment of neurological disorders.
Achieving the Goals of the Cancer Moonshot Requires Progress against All Cancers
Authors: Monica M. Bertagnolli, Danielle Carnival, Elizabeth M. Jaffee
Journal: Cancer Discovery (2023)

Summary: In February 2022, President Joseph R. Biden made reducing age-adjusted cancer mortality by at least 50% over the next 25 years a key goal of the Cancer Moonshot. Although recent progress puts this goal within reach, succeeding will require major commitments to progress on all fronts: basic research, clinical and translational research, health care delivery, and public health. See related article by Shiels et al., p. 1084 (2).
Therapeutic Development in Polyarticular Course Juvenile Idiopathic Arthritis: Extrapolation, Dose Selection, and Clinical Trial Design
Authors: Laura E. Schanberg, Lily (Yeruk) Mulugeta, Bolanle Akinlade, Hermine I. Brunner, Jianmeng Chen, Robert A. Colbert, Vincent Delgaizo, Marc R. Gastonguay, Rachel Glaser, Lisa Imundo, Daniel J. Lovell, Jocelyn H. Leu, Nael M. Mostafa, Robert M. Nelson, Peter A. Nigrovic, Nikolay P. Nikolov, Lisa G. Rider, Rebecca Rothwell, Chandrahas Sahajwalla, Renu Singh, Vikram Sinha, Carolyn L. Yancey, Lynne Yao
Journal: Arthritis & Rheumatology (2023)

Stakeholders met to address persistent challenges facing the development of therapeutics for polyarticular juvenile idiopathic arthritis (pJIA), which result in fewer approved therapies for children with pJIA than adults with rheumatoid arthritis (RA) and long lag times from adult RA approval to pediatric labeling. Ensuring that new medications are authorized in a timely manner to meet the needs of JIA patients worldwide is critically important to multiple stakeholders.The Food and Drug Administration in collaboration with the University of Maryland Center for Regulatory Science and Innovation held a public workshop entitled "Accelerating Drug Development for pJIA" on October 2, 2019, to address challenges surrounding access to new medications for children and adolescents with pJIA. Regulatory, academic, and industry stakeholders, as well as patient representatives, participated in the workshop, which consisted of 4 sessions, including panel discussions.The workshop facilitated broad public discussion of challenges facing the development of pJIA therapeutics, highlighting areas of need and outlining opportunities to expedite development, while underscoring the necessity of close collaboration between all stakeholders, including patients and families.This report summarizes key aspects of the workshop, including the appropriate application of innovative approaches to the development of pJIA therapeutics, including extrapolation, to address current challenges and provide timely access to newer safe and effective treatments. Long-term safety assessment is of pressing concern to stakeholders and cannot be fully extrapolated from adult studies but requires consistent postmarketing long-term follow-up.
Potential global impact of <scp>sodium–glucose</scp> cotransporter‐2 inhibitors in heart failure
Authors: Khawaja M. Talha, Javed Butler, Stephen J. Greene, Rahul Aggarwal, Stefan D. Anker, Brian L. Claggett, Kieran F. Docherty, Scott D. Solomon, John J.V. McMurray, James L. Januzzi, Muthiah Vaduganathan, Gregg C. Fonarow
Journal: European Journal of Heart Failure (2023)
A View on Drug Development for Cancer Prevention
Authors: Andrew R. Reynolds, Michele Moschetta, Alula R. Yohannes, Farzana Walcott, Marianne Ashford, Zoltan Szucs, Tina Sarbajna, James Hadfield, Eden Harrison, Benjamin G. Challis, Amaya Gasco Hernandez, Gaia Schiavon, Caroline Germa, Gyorgy Zorenyi, Barry Crean, Susan Galbraith
Journal: Cancer Discovery (2023)

Abstract Despite some notable successes, there are still relatively few agents approved for cancer prevention. Here we review progress thus far in the development of medicines for cancer prevention, and we outline some key concepts that could further enable or accelerate drug development for cancer prevention in the future. These are summarized under six key themes: (i) unmet clinical need, (ii) patient identification, (iii) risk stratification, (iv) pharmacological intervention, (v) clinical trials, and (vi) health care policy. These concepts, if successfully realized, may help to increase the number of medicines available for cancer prevention. Significance: The huge potential public health benefits of preventing cancer, combined with recent advances in the availability of novel early detection technologies and new treatment modalities, has caused us to revisit the opportunities and challenges associated with developing medicines to prevent cancer. Here we review progress in the field of developing medicines to prevent cancer to date, and we present a series of ideas that might help in the development of more medicines to prevent cancer in the future.
An Unusual Cause of ST-Segment Elevation in the Right Precordial Leads—A Clue From the Humble Waves
Authors: Yan Chen, Gujiang Chen, Yuan Zhang
Journal: JAMA Internal Medicine (2023)

This case report describes a patient in their late teens who presented to the outpatient department stating that they had felt the implanted cardioverter defibrillator deliver a shock 3 times within the past 6 months.
Errors in Figure 2
Journal: JAMA Network Open (2023)

Errors in Figure 2 In the Original Investigation titled "Trends in Supply of Nursing Home Beds, 2011-2019," 1 published March 1, 2023, there is an error in Panel C of Figure 2. The figure should have shown the mean number of beds adjusted per 10 000 per county by year instead of the sum of all the number of beds adjusted per 10 000 in each county by year.This article has been corrected.